Huntington’s disease patients get first dosing in historic Isis Pharmaceuticals’ gene-silencing drug trial

Huntington’s disease patients in England have received the first dosing of an Isis Pharmaceuticals drug, ISIS-HTT_Rx, aimed at stopping the disease at its genetic roots.

The patients displayed no immediate complications. This so far confirms expectations that the gene-silencing drug would be safe to use, although clinical trial administrators will continue to make critical observations in the coming months. Other dosings will occur. The drug’s efficacy will not be analyzed until later stages of the trial.

An announcement came October 19 that a small number of Phase I clinical trial participants at University College London (UCL), the lead site for study, had received injections via spinal cord of the Isis compound, according to a UCL news release.

“It's the beginning of quite an important journey in Huntington's disease,” Sarah Tabrizi, Ph.D., the director of UCL’s Huntington's Disease Centre and the global chief clinical investigator for the trial, told the BBC. “It is clearly very early but this is a step forward.

“The preclinical work shows that if you lower production of the mutant protein then animals recover a large amount of motor function. Huntington's is a really terrible disease that blights families. I know a mother whose husband and three children were affected. This would have a massive impact [if it works].”

Sarah Tabrizi, Ph.D. (photo from University College London website)

Slowing or preventing the disease

The news comes just three months after Isis announced the official start of the trial, the first time HD patients are receiving a substance aimed to attack the genetic causes of the disease. Isis has partnered with the Swiss-based pharmaceutical giant Roche to facilitate the clinical trial and, if it’s successful, the marketing of the drug.

Isis officials were unavailable for comment on October 19 but the main scientist spearheading the development of ISIS-HTT_Rx, which signifies a medication for HD, commented in the UCL release.

“We designed ISIS-HTT_Rx to target the huntingtin gene and reduce the production of huntingtin protein, which is the known cause of the disease,” stated Frank Bennett, Ph.D., the Isis senior vice president for research. “This approach has the potential to prevent or slow the progression of this disease. If this first-in-human trial proves the drug is safe, we look forward to continuing our successful partnership with Roche to bring the drug to market.”

Dr. Bennett has previously described the drug, scientifically known as an antisense oligonucleotide (oligo), as a “laser-guided missile” targeting a “specific messenger RNA that causes a particular disease and kill it or take it out of the body so that you don’t produce that messenger RNA.”

Isis announced the details of the trial in August 2014 (click here to read more).

Frank Bennett, Ph.D., senior vice president for research at Isis Pharmaceuticals (photo by Dr. Ed Wild)

Safety and tolerability first

The Phase I trial involves patients at UCL and also at various sites in Canada and Germany. Across all sites, a total of about 36 patients will take part. Phase I trials focus primarily on the safety and tolerability of a drug. The study will also help determine the frequency and size of dosages for eventual Phase II and Phase III trials, which measure efficacy.

All of the volunteers have early stage HD. Because of the use of spinal taps to administer the drug and the highly experimental nature of the oligos, no non-HD-affected individuals are taking part as controls.

No announcements have yet been made about dosing of patients in Canada and Germany.

According to the UCL release, the ISIS-HTT_Rx is taking place in the new Leonard Wolfson Experimental Neurology Centre, a custom-built facility designed to accelerate innovative treatments for neurodegenerative diseases.

“The administration of the first doses of ISIS-HTT_Rx marks the Centre's first use as a phase 1 'first into human' trial facility, as well as the first time that an experimental drug has been given by spinal injection in the 156-year history of the National Hospital for Neurology and Neurosurgery, part of University College London Hospitals (UCLH) NHS Foundation Trust,” the release stated.

What’s next?

“The first volunteers have been treated without any immediate complications,” the scientist-written HD research site HDBuzz observed. “The next year or so will be a period of intense study of these trial volunteers to make sure that they don’t have unexpected complications from the treatment. They’ll also be examined for a range of measures of whether or not the drug is working, which will provide critical information for planning future HD gene silencing studies.”

Depending on the pace of recruitment, Phase I most likely will end in 2017. If Phase I is successful, Phase II could follow no sooner than nine months later. All three phases of a clinical trial program typically take at least five years.

Historically, only ten percent of clinical trials ever result in a marketable drug.

Regardless, the HD community has crossed a significant threshold. Science has yet to produce an effective treatment for HD, as well as for Alzheimer’s, Parkinson’s, and other neurological disorders. HD could be the first.

Hope is palpable.

As a carrier of the deadly HD gene who lost his mother to the disease in 2006 and has tracked the Isis project since 2007, I am thrilled that our fellow HD community members have successfully made the first step in this historic clinical trial. They deserve our enthusiastic applause for volunteering.

(Disclosure: I hold a symbolic amount of Isis shares.)

At-risk Angels pitcher Joe Smith at Huntington’s fundraiser: ‘I’d give every dime I have for a cure’

No one person is the face of Huntington’s disease the way ALS is associated with Lou Gehrig or Parkinson’s disease is linked with Michael J. Fox. But HD touches many lives, including some we know from major league sports.

Choking back tears, 31-year-old Los Angeles Angels baseball pitcher Joe Smith remembered the phone call three years ago from his father back in his native Ohio that changed his life forever: his mother had been diagnosed with Huntington’s disease.

“Unfortunately, I got a call driving home from our spring training site in Goodyear, Arizona, from my dad,” Joe told an audience of over 400 people at a San Diego fundraiser on October 10. “He told me: mom had HD.”

Then Joe recalled when his mother Lee came on the phone on that day in February 2012, not long after she had received her genetic test results confirming she had HD.

“I’ll never forget the sound of her voice,” he said. “It was just empty. It was the worst. I never heard anything like it. That stayed with me for a long time, that sound, when she said, ‘Hi, Joseph,’ but the way she said it […] was different. And it hurt. It still does, obviously. This time, when she got the news, I still didn’t know a whole lot about HD. But obviously, when you get off the phone with the parents and got a 30-minute drive, there’s a lot of thinking that goes on.”

He’s done a lot of thinking – and action – since then.

For his efforts to raise awareness and funds for the HD cause, Joe received the Guthrie Award of the Huntington’s Disease Society of America (HDSA) at the San Diego chapter’s 15th Annual Celebration of Hope Gala, held this year at the spectacular coastal residence of Craig and Rebecca Irving. Craig is a businessman and philanthropist.

Above, Joe Smith and mother Lee (photo by Gene Veritas, aka Kenneth P. Serbin). Below, Celebration of Hope Gala attendees mingling before the start of dinner and the formal program (photo by Mike Nowak).

Staring HD in the face

Joe remembered his family’s four-hour drives from southern Ohio to Cleveland to visit Lee’s mother, who, the family knew, suffered from HD. Seeing his grandmother’s progressively worsening symptoms at each visit left Joe sad and concerned as a child and teenager.

“I think that’s the scariest part,” Joe continued. “It’s one thing, I think, to go through life, or to have something that not necessarily you don’t know about, but […] my mom took care of my grandma, she went to doctor visits with my grandma, she was on the phone all the time with my grandma.

“When you know the road you’re heading down, and right now there’s nothing that you can do about it, you’re just going. You’re hoping there’s light. You got hope. You got faith. But at the end of the day, right now, there’s no cure.”

Lee did not speak at the gala but talked about her symptoms in a brief video shown to the audience.

“She stares it right in the face every day,” Joe said, referring several times to his mother’s fortitude.

Joe ended his speech with a call to boost fundraising for HD research.

“I’d give every dime I have if they had a cure today,” he declared.

You can watch Joe’s speech in the video below. View other videos of the event by clicking here.

Los Angeles Angels' Joe Smith: 'I'd Give Every Dime I Have for a Cure for Huntington's Disease' from Gene Veritas on Vimeo.

Taking public action

As the children of an HD-affected parent, both Joe and his 29-year-old sister Megan Nein have a 50-50 chance of inheriting the genetic defect.

Joe has previously talked to the press about his fears of living at risk.

“My sister has three kids and she hasn't been tested,” Joe said last March. “I got married recently, and I'll get tested before we have kids.”

He didn’t speak directly about his fears at the gala, but they were palpable throughout his speech.

Both Joe's and HDSA CEO Louise Vetter’s comments once again demonstrated how HD can devastate the extended family because of its genetic cause and difficult caregiving burden.

“It’s not easy to come out and say you’re from an HD family,” Vetter said in introducing Joe. “If one of your parents has it, you don’t know if you have it or not. So it takes a lot of courage to face your future.”

Recalling Woody Guthrie’s widow Marjorie’s founding of HDSA in 1967, the organization recognized Joe with the Guthrie Award because of his “bravery” in confronting HD, she said.

Too often conversations about HD take place “behind closed doors,” Vetter observed.

The Smith family has “made it public and they’ve created a call to action,” she explained.

HDSA CEO Louise Vetter (photo by Mike Nowak)

The community emerging as its own spokesperson

For older generations of Americans, songwriter-activist Guthrie symbolized HD.

In recent decades, with younger generations unacquainted with Guthrie, many in the Huntington’s community have attributed the lack of awareness about HD – ironically one of the most common of the rare diseases – to the lack of a celebrity such as Michael J. Fox in the sphere of Parkinson’s disease.

Without national opinion polling on HD, we can’t really know if this is the case.

What’s important is that more HD family members are telling their stories publicly than ever before, and HD is gaining exposure.

Like 33-year-old filmmaker-actress Marianna Palka, who revealed her HD genetic test results in an HBO film that premiered in June, Joe is emerging as a key new spokesperson for the HD cause.

Two other successful athletes – former Olympic rower Sarah Winckless and former National Hockey League player Jake Dowell – have shared their HD stories.

In June, another, award-winning film, the documentary The Huntington’s Disease Project: Removing the Mask, was released.

Networking for the cause

Joe’s advocacy is helped by the fact that professional baseball maintains a huge fan base.

Joe and his family have started a foundation, Help Cure HD, to raise money for research on deep brain stimulation (DBS) as a potential treatment for HD. (For years doctors have used DBS to treat Parkinson’s disease.) So far Help Cure HD has raised nearly $400,000.

Joe’s wife is Allie LaForce, a TV reporter for CBS Sports. In January, Allie did a feature on Bill Johnston, the public relations director of the National Football League’s San Diego Chargers, and his fight against HD. Bill’s wife Ramona, who has HD, now lives in a nursing home.

The main mover behind the smartly produced HDSA-San Diego galas, Bill has helped raise several million dollars for HDSA through those events and numerous others.

Bill uses his contacts in the upper echelons of business and pro sports to invite speakers like Joe and garner corporate sponsors such as the B. H. Gold Insurance Agency. HDSA also honored B.H. Gold President Bill Habeger with the Guthrie Award for his support of the cause.

“May these galas soon be victory galas,” Habeger told the audience.

HDSA-San Diego President Burt Brigida (left), B.H. Gold President Bill Habeger, HDSA CEO Vetter, and HDSA-San Diego immediate past president George Essig (photo by Mike Nowak)

From the heart, emboldening our community

As they arrived at the gala, I introduced myself to Joe, Lee, Joe’s father Mike, and Tim Mead, the Angels’ vice president for communications.

I told Joe that I was also from Ohio, that my mother had died of HD, and that I carried the genetic defect. I told him that he could rely on the San Diego chapter, HDSA, and me for anything he and his family might need in the struggle against HD.

Lee and I shared a few words about our common Cleveland connection. When she mentioned that she was 56, I said I was right there with her at 55.

At 56, my own mother had the involuntary movements typical in HD and was starting to lose her ability to reason.

Joe (left), Lee, and Mike Smith with Tim Mead, vice president for communications, Los Angeles Angels (photo by Gene Veritas)

I thought of how lucky I was to remain asymptomatic and participate fully in the gala.

After his speech, Joe asked my opinion.

“You hit it right on the mark,” I said. “You spoke from the heart.”

Later, just before the end of the gala, I spoke again with Joe. “We are brothers in this cause,” I said, putting my arm around his shoulder.

Joe raised awareness and money, but most importantly he has emboldened our fellow HD brothers and sisters to join the fight. Having every dime in the world won't bring treatments unless we have enough participants in the all-crucial research studies and clinical trials.

Joe Smith (left) and Gene Veritas (photo by Mike Nowak). Watch more videos of the gala by clicking here.